Cardiovascular disease, including coronary heart disease, stroke and other vascular diseases, is the leading cause of death of men and women in economically-developed countries. The most common and lethal form of cardiovascular disease is ischemic heart disease. It has generally been regarded that ischemic heart disease is caused, primarily, by atherosclerosis of the coronary arteries. This is a condition where plaques form in the inner lining of the arteries, causing narrowing of the channel and thereby impairing blood flow to the heart.
An increased risk for ischemic heart disease is observed in women after menopause or ovariectomy and presents a major medical challenge. It is the leading cause of death in post-menopausal women, which implicates the importance of the loss of ovarian steroid hormones.
Since it is understood that the formation of plaques is reduced, or even possibly reversed, by a high ratio of high density lipoproteins (HDL) to low density lipoproteins (LDL), it has been a strategy to inhibit ischemic heart disease by attempting to increase this ratio in the blood stream. Estradiol, an ovarian estrogenic steroid hormone, has been observed to increase the HDL/LDL ratio, and studies so far suggest that estrogen replacement therapy for post-menopausal women decreases the incidence of coronary artery disease, myocardial infarction, and related cardiovascular events by up to 50%.
A vasospasm is an abnormally strong and persistent contraction of the muscles of the coronary arteries which leads to transmural myocardial ischemia and can result in sudden cardiac death. The role of coronary vasospasm in cardiovascular disease is still controversial, and approaches to treatments for cardiovascular disease have not focused upon methods for reducing coronary vasospasm. Instead, it is generally believed that coronary vasospasm is caused by local injury to vessels, such as results from atherosclerosis and other structural injury, and that long-term treatment of cardiovascular disease requires prevention of atherosclerotic plaques, not treatments to prevent vasospasm.
Hermsmeyer, U.S. Pat. No. 6,056,972, incorporated herein by reference and referred to hereafter as the “Hermsmeyer patent”, discloses that low levels of progesterone, either alone or in combination with estradiol, can inhibit coronary artery reactivity by a direct effect on coronary arteries and, therefore, can be used to inhibit certain adverse cardiovascular events and disorders. Progesterone, administered in conjunction with estradiol, dramatically reduces the incidence of the adverse effects of unopposed estrogen. Hermsmeyer discloses that coronary artery vasospasm can be prevented by administering to a subject progesterone in an amount to achieve blood levels of progesterone of between 0.1 nanograms/ml and less than 4 nanograms/ml for at least 4 hours per day, and wherein said amount results in peak levels of progesterone of less than 6 nanograms/ml. Hermsmeyer further discloses that progesterone may be used to treat an existing vasospasm.
Hermsmeyer discloses that exaggerated vasoconstrictions of long (greater than 5 minute) duration are reliably initiated in the presence of estrogen and progesterone deficiency by the synergistic combination of two major platelet release products, serotonin and thromboxane A2 at concentrations found in platelets. Hermsmeyer discloses that administration of these two compounds to menopausal monkeys produces intense, focal constrictions that mimic arterial vasoconstrictions in humans. These severe induced vasoconstrictions are prevented or terminated by the administration of estradiol and/or progesterone.